Supplementation
Position Stand
2017
International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine
By Richard B. Kreider, Douglas S. Kalman, Jose Antonio, Tim N. Ziegenfuss, Robert Wildman, Rick Collins, Darren G. Candow, Susan M. Kleiner, Anthony L. Almada and Hector L. Lopez
Journal of the International Society of Sports Nutrition, 14, pp. 18
Abstract
<h1>Abstract</h1> <p><a href="/terms/creatine-monohydrate/" class="term-link" data-slug="creatine-monohydrate" title="Creatine">Creatine</a> is one of the most popular nutritional ergogenic aids for athletes. Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations which may help explain the observed improvements in high intensity exercise performance leading to greater training adaptations. In addition to athletic and exercise improvement, research has shown that creatine supplementation may enhance post-exercise recovery, injury prevention, thermoregulation, rehabilitation, and concussion and/or spinal cord neuroprotection. Additionally, a number of clinical applications of creatine supplementation have been studied involving neurodegenerative diseases (e.g., muscular dystrophy, Parkinson's, Huntington's disease), diabetes, osteoarthritis, fibromyalgia, aging, brain and heart ischemia, adolescent depression, and pregnancy. These studies provide a large body of evidence that creatine can not only improve exercise performance, but can play a role in preventing and/or reducing the severity of injury, enhancing rehabilitation from injuries, and helping athletes tolerate heavy training loads. Additionally, researchers have identified a number of potentially beneficial clinical uses of creatine supplementation. These studies show that short and long-term supplementation (up to 30 g/day for 5 years) is safe and well-tolerated in healthy individuals and in a number of patient populations ranging from infants to the elderly. Moreover, significant health benefits may be provided by ensuring habitual low dietary creatine ingestion (e.g., 3 g/day) throughout the lifespan. The purpose of this review is to provide an update to the current literature regarding the role and safety of creatine supplementation in exercise, sport, and medicine and to update the position stand of International Society of Sports Nutrition (ISSN).</p> <p><strong>Keywords:</strong> Ergogenic aids, Performance enhancement, Sport nutrition, Athletes, Muscular strength, Muscle power, Clinical applications, Safety, Children, Adolescents</p>Background
<h1>Background</h1> <p><a href="/terms/creatine-monohydrate/" class="term-link" data-slug="creatine-monohydrate" title="Creatine">Creatine</a> is one of the most popular nutritional ergogenic aids for athletes. Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations, can improve exercise performance, and/or improve training adaptations. Research has indicated that creatine supplementation may enhance post-exercise recovery, injury prevention, thermoregulation, rehabilitation, and concussion and/or spinal cord neuroprotection. A number of clinical applications of creatine supplementation have also been studied involving neurodegenerative diseases (e.g., muscular dystrophy, Parkinson's, Huntington's disease), diabetes, osteoarthritis, fibromyalgia, aging, brain and heart ischemia, adolescent depression, and pregnancy. The purpose of this review is to provide an update to the current literature regarding the role and safety of creatine supplementation in exercise, sport, and medicine and to update the position stand of International Society of Sports Nutrition (ISSN) related to creatine supplementation.</p>Metabolic Role
<h1>Metabolic Role</h1> <p><a href="/terms/creatine-monohydrate/" class="term-link" data-slug="creatine-monohydrate" title="Creatine">Creatine</a>, a member of the guanidine phosphagen family, is a naturally occurring non-protein amino acid compound found primarily in red meat and seafood [1–4]. The majority of creatine is found in skeletal muscle (~95%) with small amounts also found in the brain and testes (~5%) [5, 6]. About two thirds of intramuscular creatine is <a href="/terms/phosphocreatine/" class="term-link" data-slug="phosphocreatine" title="phosphocreatine">phosphocreatine</a> (PCr) with the remaining being free creatine. The total creatine pool (PCr + Cr) in the muscle averages about 120 mmol/kg of dry muscle mass for a 70 kg individual [7]. However, the upper limit of creatine storage appears to be about 160 mmol/kg of dry muscle mass in most individuals [7, 8]. About 1–2% of intramuscular creatine is degraded into creatinine (metabolic byproduct) and excreted in the urine [7, 9, 10]. Therefore, the body needs to replenish about 1–3 g of creatine per day to maintain normal (unsupplemented) creatine stores depending on muscle mass. About half of the daily need for creatine is obtained from the diet [11]. For example, a pound of uncooked beef and salmon provides about 1–2 g of creatine [9]. The remaining amount of creatine is synthesized primarily in the liver and kidneys from arginine and glycine by the enzyme arginine:glycine amidinotransferase (AGAT) to guanidinoacetate (GAA), which is then methylated by guanidinoacetate N-methyltransferase (GAMT) using S-adenosyl methionine to form creatine [12].</p> <p>Some individuals have been found to have creatine synthesis deficiencies due to inborn errors in AGAT, GMAT and/or creatine transporter (CRTR) deficiencies and therefore must depend on dietary creatine intake in order to maintain normal muscle and brain concentrations of PCr and Cr [13–19]. Vegetarians have been reported to have lower intramuscular creatine stores (90–110 mmol/kg of dry muscle) and therefore may observe greater gains in muscle creatine content from creatine supplementation [11, 13, 20, 21]. Conversely, larger athletes engaged in intense training may need to consume 5–10 g/day of creatine to maintain optimal or capacity whole body creatine stores [22] and clinical populations may need to consume 10–30 g/day throughout their lifespan to offset creatine synthesis deficiencies and/or provide therapeutic benefit in various disease states [13, 19, 23].</p> <p>Phosphagens are prevalent in all species and play an important role in maintaining energy availability [1, 2, 24, 25]. The primary metabolic role of creatine is to combine with a phosphoryl group (Pi) to form PCr through the enzymatic reaction of creatine kinase (CK). Wallimann and colleagues [26–28] suggested that the pleiotropic effects of Cr are mostly related to the functions of CK and PCr (i.e., CK/PCr system). As <a href="/terms/adenosine-triphosphate/" class="term-link" data-slug="adenosine-triphosphate" title="adenosine triphosphate">adenosine triphosphate</a> (ATP) is degraded into adenosine diphosphate (ADP) and Pi to provide free energy for metabolic activity, the free energy released from the hydrolysis of PCr into Cr + Pi can be used as a buffer to resynthesize ATP [24, 25]. This helps maintain ATP availability particularly during maximal effort anaerobic sprint-type exercise. The CK/PCr system also plays an important role in shuttling intracellular energy from the mitochondria into the cytosol. The CK/PCr energy shuttle connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases) [24, 25, 27]. In this regard, creatine enters the cytosol through a CRTR [16, 29–31]. In the cytosol, creatine and associated cytosolic and glycolytic CK isoforms help maintain glycolytic ATP levels, the cytosolic ATP/ADP ratio, and cytosolic ATP-consumption [27]. Additionally, creatine diffuses into the mitochondria and couples with ATP produced from oxidative phosphorylation and the adenine nucleotide translocator (ANT) via mitochondrial CK. ATP and PCr can then diffuse back into the cytosol and help buffer energy needs. This coupling also reduces the formation of reactive oxygen species (ROS) and can therefore act as a direct and/or indirect antioxidant [32–35]. The CK/PCr energy shuttle thereby connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases) in order to fuel energy metabolism [24, 25, 27]. In this way, the CK/PCr system thereby serves as an important regulator of metabolism which may help explain the ergogenic and potential therapeutic health benefits of creatine supplementation [4, 27, 33, 36–45].</p>Supplementation Protocols
<h1>Supplementation Protocols</h1> <p>In a normal diet that contains 1–2 g/day of <a href="/terms/creatine-monohydrate/" class="term-link" data-slug="creatine-monohydrate" title="creatine">creatine</a>, muscle creatine stores are about 60–80% saturated. Therefore, dietary supplementation of creatine serves to increase muscle creatine and <a href="/terms/phosphocreatine/" class="term-link" data-slug="phosphocreatine" title="PCr">PCr</a> by 20–40% [7, 8, 10, 46–48]. The most effective way to increase muscle creatine stores is to ingest 5 g of creatine monohydrate (or approximately 0.3 g/kg body weight) four times daily for 5–7 days [7, 10]. However, higher levels of creatine supplementation for longer periods of time may be needed to increase brain concentrations of creatine, offset creatine synthesis deficiencies, or influence disease states [13, 19, 23]. Once muscle creatine stores are fully saturated, creatine stores can generally be maintained by ingesting 3–5 g/day, although some studies indicate that larger athletes may need to ingest as much as 5–10 g/day in order to maintain creatine stores [7, 8, 10, 46–48]. Ingesting creatine with carbohydrate or carbohydrate and protein have been reported to more consistently promote greater creatine retention [8, 22, 49, 50]. An alternative supplementation protocol is to ingest 3 g/day of creatine monohydrate for 28 days [7]. However, this method would only result in a gradual increase in muscle creatine content compared to the more rapid loading method and may therefore have less effect on exercise performance and/or training adaptations until creatine stores are fully saturated. Research has shown that once creatine stores in the muscle are elevated, it generally takes 4–6 weeks for creatine stores to return to baseline [7, 48, 51]. Additionally, it has been recommended that due to the health benefits of creatine, individuals should consume about 3 g/day of creatine in their diet particularly as one ages [27]. No evidence has suggested that muscle creatine levels fall below baseline after cessation of creatine supplementation; therefore, the potential for long-term suppression of endogenous creatine synthesis does not appear to occur [22, 52].</p>Bioavailability
<h1>Bioavailability</h1> <p>The most commonly studied form of <a href="/terms/creatine-monohydrate/" class="term-link" data-slug="creatine-monohydrate" title="creatine">creatine</a> in the literature is creatine monohydrate [53]. The uptake of creatine involves the absorption of creatine into the blood and then uptake by the target tissue [53]. Plasma levels of creatine typically peak at about 60 min after oral ingestion of creatine monohydrate [7]. An initial rise in plasma creatine levels, followed by a reduction in plasma levels can be used to indirectly suggest increased uptake into the target tissue [53]. However, the gold standards for measuring the effects of creatine supplementation on target tissues are through magnetic resonance spectroscopy (MRS), muscle biopsy, stable isotope tracer studies, and/or whole body creatine retention assessed by measuring the difference between creatine intake and urinary excretion of creatine [53].</p> <p>Creatine is stable in solid form but not in aqueous solution due to an intramolecular cyclization [54]. Generally, creatine is converted to creatinine at higher rates the lower the pH and the higher the temperature. For example, research has shown that creatine is relatively stable in solution at neutral pH (7.5 or 6.5). However, after 3 days of storage at 25 °C, creatine degrades to creatinine (e.g., 4% at pH 5.5; 12% at pH 4.5; and 21% at pH 3.5) [53, 55]. The degradation of creatine into creatinine over time is the main reason that creatine is sold in solid form. However, this does not mean that creatine is degraded into creatinine in vivo through the digestive process. In this regard, the degradation of creatine to creatinine can be reduced or halted by either lowering the pH under 2.5 or increasing the pH [53]. A very low pH results in the protonation of the amide function of the creatine molecule, thereby preventing the intramolecular cyclization [53]. Therefore, the conversion of creatine to creatinine in the gastrointestinal tract is minimal regardless of transit time; absorption into the blood is nearly 100% [10, 53, 56, 57].</p> <p>The vast majority of studies assessing the efficacy of creatine supplementation on muscle phosphagen levels, whole body creatine retention, and/or performance have evaluated creatine monohydrate. Claims that different forms of creatine are degraded to a lesser degree than creatine monohydrate in vivo or result in a greater uptake to muscle are currently unfounded [53]. Clinical evidence has not demonstrated that different forms of creatine such as creatine citrate [50], creatine serum [58], creatine ethyl ester [59], buffered forms of creatine [60], or creatine nitrate [61] promote greater creatine retention than creatine monohydrate [53].</p>관련 논문
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